Opinion
EDITORIAL
Clinical Trials in Idiopathic Pulmonary Fibrosis
in the“Posttreatment Era”
Kevin F. Gibson, MD; Daniel J. Kass, MD
The “treatment era” for idiopathic pulmonary fibrosis (IPF) in
the United States and other countries was inaugurated in No-
vember 2014 following the Food and Drug Administration’s
(FDA’s) approval of pirfenidone and nintedanib as treatments
for IPF.1 Even the most opti-
mistic pulmonologists may
Related article have doubted that such a day
would ever arrive, let alone a
day when a practicing clinician would have not 1, but 2 medi-
cations to treat IPF. The FDA approved pirfenidone and nin-
tedanib on the basis of published studies that showed these
therapies slowed the rate of deterioration of forced vital ca-
pacity (FVC).2,3
The change in FVC, referred to as a clinically meaningful end
point in IPF,4,5 is used as a surrogate for the ultimate question
in IPF—does therapy stop progression and improve survival? The
clinician prescribing these medications is left with the unsat-
isfying published results that neither nintedanib nor pirfeni-
done convincingly enhance survival or improve quality of life.
However, the pirfenidone and nintedanib studies were not pow-
ered to detect changes in mortality,6 and it is unlikely that any
IPF trial will ever focus on mortality.7 How to design IPF clini-
cal studies has often been debated.4,5 Nevertheless and aside
from the academic debates over IPF trial design, the concerns
about adverse effects in older patients, combined with uncer-
tain therapeutic outcomes, give many clinicians pause when
considering prescribing these new drugs. Diarrhea occurred in
61.5% of patients treated with nintedanib, and nausea oc-
curred in 36% of pirfenidone-treated patients.2,3
In this issue of JAMA, Raghu and colleagues8 report the
results of a phase 2 randomized clinical trial that tested re-
combinant human pentraxin 2 (also known as PRM-151) vs pla-
cebo in patients with IPF. A smaller clinical trial (reported in
2016) showed that treatment with recombinant human pen-
traxin 2 was relatively safe, increased plasma levels of pen-
traxin 2, and was associated with a nonsignificant (and very
modest) improvement in FVC and 6-minute walk distance.9
In the study by Raghu et al,8 117 patients with a clinical di-
agnosis of IPF, based on 2011 guidelines,10 were included if they
had FVC between 50% and 90% and diffusing capacity for car-
bon monoxide (DLCO) between 25% and 90% predicted. Con-
current therapy with current FDA-approved medications was
permitted if the dosing was stable for 3 months. Following a
4-week screening period, patients were then randomized to
receive 4 intravenous infusions of drug (10 mg/kg) every 4
weeks or placebo. Patients were followed up for 24 weeks. The
primary outcome was mean change in FVC (% predicted value)
jama.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Universita Cattolica del Sacro Cuore User on 05/23/2018
from baseline to week 28. Secondary end points included volu-
metric analysis using high-resolution computed tomo-
graphic scanning and change in 6-minute walk distance.
At week 28, the change in FVC (% predicted value) among
patients treated with placebo was −4.8 compared with −2.5
among patients treated with recombinant human pentraxin 2
(mean difference, 2.3 [90% CI, 1.1-3.5]; P = .001). Among sec-
ondary end points, the change in 6-minute walk distance was
−0.5 m among patients treated with recombinant human pen-
traxin 2 compared with −31.8 m in patients treated with pla-
cebo (difference, 31.3 m [90% CI, 17.4-45.1]; P < .001). The study
showed that the rate of deterioration of FVC percentage of pre-
dicted value was significantly slower in the recombinant hu-
man pentraxin 2 group vs the placebo group. The authors noted
the rate of adverse events was similar between the placebo
group and drug treatment group. Cough was observed more
frequently among patients in the recombinant human pen-
traxin 2 group (18%) than the placebo group (5%).
The findings reported by Raghu et al8 are cause for opti-
mism. A strong body of mechanistic evidence supports the po-
tential efficacy of the drug. Pentraxin 2 knockout mice devel-
oped exaggerated bleomycin-induced pulmonary fibrosis.11 In
a murine model of kidney fibrosis, recombinant human pen-
traxin 2 was associated with decreased kidney failure, im-
proved histology, and improved survival.12 Collectively, the ex-
perimental research has elucidated both a potential receptor
and signaling pathway. In macrophages and epithelial cells, re-
combinant human pentraxin 2 attenuated activator protein-1
signaling activity.12 In the lung, stimulation of a novel puta-
tive receptor for pentraxin 2, DC-SIGN (dendritic cell–specific
intercellular adhesion molecule-3-grabbing nonintegrin), which
is present on monocytes and neutrophils, attenuated fibro-
cyte differentiation and collagen deposition in bleomycin-
injured mice.13 However, further mechanistic studies14 are
needed to help determine ways that the parent compound can
be enhanced for therapeutic efficacy. In the case of pirfeni-
done and nintedanib, comparable mechanistic data are
lacking.14 A bedside-to-bench approach could leverage the re-
sults of clinical trials to guide basic science researchers to study
mechanisms that clearly affect clinical phenotypes.
Despite the impressive results of this phase 2 trial reported
by Raghu et al,8 the next step is for recombinant human pentraxin
2 to proceed to phase 3. The investigators are experienced IPF tri-
alists who recognize the need for further research and present a
balanced discussion that illustrates restrained excitement. Suc-
cess in phase 2 studies of agents with strong biological rationale
does not necessarily portend success in phase 3 trials. Accepting
(Reprinted) JAMA Published online May 20, 2018 E1
 Opinion Editorial

this caveat, what would a phase 3 clinical trial for recombinant
human pentraxin 2 in patients with IPF look like? The investiga-
tors will have to consider these questions carefully.
The current standard-of-care drugs met the clinically mean-
ingful end point in their respective studies. But the current clini-
cally meaningful end point may not necessarily be a clinically use-
ful end point. A phase 3 trial for recombinant human pentraxin
2 would represent one of the first phase 3 trials for a new agent
in IPF since the onset of this so-called treatment era. It has been
well-documented that a multiyear trial in IPF, powered to detect
a survival benefit, is not feasible.7 However, if event rates in IPF
are low after 1 year of observation, perhaps a phase 3 trial should
continue for 18 or even 24 months.
The authors also note the intriguing result for the second-
ary outcome of 6-minute walk distance. At first glance, it would
appear that the investigators should power a phase 3 study to
detect changes in 6-minute walk distance as a primary end
point. After all, would a test of exercise capacity, with all of its
presumed implications for patient independence and well-
being, not be meaningful? The authors cite studies that dem-
onstrate that the change in 6-minute walk distance may be a
critical prognostic factor in IPF,15,16 but they also note poten-
tially diminished enthusiasm for this end point because 6-min-
ute walk distance only weakly correlates with FVC, DLCO, or
dyspnea and may be associated with other confounders.5
Sole reliance on a 10% change in FVC and a trend toward
improved survival (as suggested by the FDA5) as the primary
outcome measure will leave the pulmonary community with-
out clear and coherent guidelines for treatment. This will be
an issue for recombinant human pentraxin 2 or for any other
agent. Because there is currently an unprecedented interest
from pharmaceutical companies to study IPF, the results of this
study underscore how the choice of end points must be settled
now. More drug candidates are on the way.
There is definitely just cause for optimism for the manage-
ment of IPF. Raghu et al8 have tested a new drug, with a solid
mechanistic rationale, in a broad and representative popula-
tion of IPF patients, and with a screen failure rate that was nearly
3-fold lower than for the ASCEND trial.3 In this population of pa-
tients with IPF, the authors have demonstrated efficacy of re-
combinant human pentraxin 2 in a phase 2 investigation. Based
on available data and the current standards of care, the first drugs
to demonstrate efficacy for any end point in IPF14 do not im-
prove survival or improve quality of life in patients with IPF. As
investigators evaluating recombinant human pentraxin 2 tran-
sition to phase 3, any follow-up study should include ancillary
translational and biomarker studies to help determine relevant
mechanisms and discover possible novel end points.
Furthermore, researchers who study IPF and clinicians in-
volved in caring for patients with IPF must establish a compos-
ite end point to address change in pulmonary function as well
as other end points for which treated patients will experience
tangible benefits. These include, but are not limited to exercise
capacity, quality of life, or survival to transplant. Admittedly,
powering a clinical trial for a composite end point is not straight-
forward, but an IPF therapy that improves or at least stabilizes
exercise capacity would be attractive and clinically useful. There-
fore, the phase 3 trial that emerges from the findings in the study
by Raghu et al8 will be particularly important and will serve as a
bellwether for the conduct of trials in a posttreatment era in IPF.

ARTICLE INFORMATION
Author Affiliations: Dorothy P. and Richard P.
Simmons Center for Interstitial Lung Disease,
University of Pittsburgh, Pittsburgh, Pennsylvania.
Corresponding Author: Daniel J. Kass, MD,
Dorothy P. and Richard P. Simmons Center for
Interstitial Lung Disease, Division of Pulmonary,
Allergy, and Critical Care Medicine, Montefiore
University Hospital NW628, 3459 Fifth Ave,
Pittsburgh, PA 15213 (kassd2@upmc.edu).
Published Online: May 20, 2018.
doi:10.1001/jama.2018.6225
Conflict of Interest Disclosures: Both authors
have completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Kass
reports receipt of collaborative research funding in
pulmonary hypertension from Regeneron
Pharmaceuticals. Dr Gibson reports having served
as a consultant to Bayer Pharmaceuticals.
Funding/Support: This work was supported by a
grant from the National Institutes of Health (NIH)
(R01 HL126990) to Dr Kass.
Role of the Funder/Sponsor: The NIH had no role
in the preparation, review, or approval of the
manuscript.
REFERENCES
1. Collard HR, Bradford WZ, Cottin V, et al. A new
era in idiopathic pulmonary fibrosis: considerations
for future clinical trials. Eur Respir J. 2015;46(1):243-
249.
2. Richeldi L, du Bois RM, Raghu G, et al. Efficacy
and safety of nintedanib in idiopathic pulmonary
fibrosis. N Engl J Med. 2014;370(22):2071-2082.
3. King TE Jr, Bradford WZ, Castro-Bernardini S,
et al; ASCEND Study Group. A phase 3 trial of
pirfenidone in patients with idiopathic pulmonary
fibrosis. N Engl J Med. 2014;370(22):2083-2092.
4. Raghu G, Collard HR, Anstrom KJ, et al.
Idiopathic pulmonary fibrosis: clinically meaningful
primary endpoints in phase 3 clinical trials. Am J
Respir Crit Care Med. 2012;185(10):1044-1048.
5. Wells AU, Behr J, Costabel U, et al. Hot of the
breath: mortality as a primary end-point in IPF
treatment trials. Thorax. 2012;67(11):938-940.
6. Brown KK. Counterpoint: should all patients with
idiopathicpulmonaryfibrosis,eventhosewithmorethan
moderate impairment, be treated with nintedanib or
pirfenidone? no. Chest. 2016;150(2):276-278.
7. King TE Jr, Albera C, Bradford WZ, et al. All-cause
mortality rate in patients with idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med. 2014;189(7):
825-831.
8. Raghu G, van den Blink B, Hamblin MJ, et al.
Effect of recombinant human pentraxin 2 vs
placebo on change in forced vital capacity in
patients with idiopathic pulmonary fibrosis:
a randomized clinical trial [published online May 20,
2018]. JAMA. doi:10.1001/jama.2018.6129
9. van den Blink B, Dillingh MR, Ginns LC, et al.
Recombinant human pentraxin-2 therapy in
patients with idiopathic pulmonary fibrosis. Eur
Respir J. 2016;47(3):889-897.
10. Raghu G, Collard HR, Egan JJ, et al. An official
ATS/ERS/JRS/ALAT statement: idiopathic
pulmonary fibrosis: evidence-based guidelines for
diagnosis and management. Am J Respir Crit Care
Med. 2011;183(6):788-824.
11. Pilling D, Gomer RH. Persistent lung
inflammation and fibrosis in serum amyloid P
component (APCs-/-) knockout mice. PLoS One.
2014;9(4):e93730.
12. Nakagawa N, Barron L, Gomez IG, et al.
Pentraxin-2 suppresses c-Jun/AP-1 signaling to
inhibit progressive fibrotic disease. JCI Insight.
2016;1(20):e87446.
13. Cox N, Pilling D, Gomer RH. DC-SIGN activation
mediates the differential effects of SAP and CRP on
the innate immune system and inhibits fibrosis in
mice. Proc Natl Acad Sci U S A. 2015;112(27):8385-8390.
14. Bahudhanapati H, Kass DJ. Unwinding the
collagen fibrils: elucidating the mechanism of
pirfenidone and nintedanib in pulmonary fibrosis.
Am J Respir Cell Mol Biol. 2017;57(1):10-11.
15. du Bois RM, Weycker D, Albera C, et al.
Six-minute-walk test in idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med. 2011;183(9):
1231-1237.
16. du Bois RM, Albera C, Bradford WZ, et al.
6-Minute walk distance is an independent predictor
of mortality in patients with idiopathic pulmonary
fibrosis. Eur Respir J. 2014;43(5):1421-1429.

E2 JAMA Published online May 20, 2018 (Reprinted) jama.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Universita Cattolica del Sacro Cuore User on 05/23/2018